P39 DEDALO: PHASE II STUDY OF DARATUMUMAB PLUS POMALIDOMIDE AND DEXAMETHASONE (DPD) IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA AND 17P DELETION
Authors: V. Montefusco, A.M. Cafro, G. Margiotta Casaluci, F. Patriarca, R. Mina, M. D’Agostino, A. Capra, C. Priola, B. Dalla Palma, R. Rizzi, A. Genua, M.T. Petrucci, L. Paris, A. Belotti, M. Cavo, C. Conticello, C. Carlo-Stella, M Boccadoro
Journal: HemaSphere (2023)

Introduction: Deletion of the short arm of chromosome 17 (del(17p)) is a well-established high-risk feature in multiple myeloma (MM) and is included in current disease staging criteria. Treatment of del(17p) MM is a major challenge due to rapid development of chemoresistance and short survival. The size of del(17p) clone correlates with prognosis, and the 55-60% threshold has the worst prognosis. Approximately 1/3 of pts have a concomitant TP53 mutation, with a complete abolition of the protein function. TP53 biallelic inactivation is defined as double-hit myeloma. Pomalidomide-dexamethasone showed promising results in this setting (Leleu et al, Blood 2014). Daratumumab is an attractive strategy for treatment of MM pts with del(17p). In the phase II DEDALO trial (NCT04124497), we assessed daratumumab-pomalidomide-dexamethasone (DPd) in RRMM pts with del(17p). Methods: Key eligibility criteria included: RRMM; up to 3 prior lines of therapy, del(17p) observed by FISH in at least 10% of plasma cells at any time of MM history, previous exposure to lenalidomide, no refractoriness or intolerance to pomalidomide, nor previous exposure to an anti-CD38 monoclonal antibody. Continuous DPd treatment consisted of daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter; oral pomalidomide (4 mg, once daily on days 1–21); and oral or intravenous dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for pts ≥75 years) at each 28-day cycle. The primary endpoint was MRD 10-5 negativity within the first 12 months of treatment. NGF and NGS MRD analyses were performed. The key secondary endpoints were PFS, ORR and OS. Results: Forty-five pts were enrolled. The median age was 63 (range 43-83) years (yrs), and 60%/29%/11% of pts had ISS stage I/II/III. All pts had >10% del(17p) and 14 pts had ≥55% del(17p); t(4;14) was observed in 6, t(14;16) in 6, del(1p) in 10, and 1q+ in 16 pts. Median number of prior lines of therapy was 1 (range 1-3); 100% had been previously exposed to lenalidomide and 86% to a proteasome inhibitor. Three pts achieved MRD negativity by NGF, while NGS analysis is ongoing. ORR was 60%, including 13 pts with PR, 12 with VGPR, and 2 with ≥CR. Median time-to-response was 2.5 months. With a median follow-up of 8.5 months (range 6.3-13.9), median PFS was 7.1 months (range 5.9 – not reached [NR]; Figure). By subgroup analysis, PFS was: 8.4 months in pts with del(17p) clone size <60% and 6.5 months in pts with del(17p) clone size ≥60% (HR, 0.75; 95% CI 0.33-1.7; P=0.48); 12.4 months in pts with ISS I vs 4.2 months in pts with ISS II-III (HR, 2.48; 95% CI 1.12-5.51; P=0.02); 6.6 months in pts at first relapse vs 7.1 months beyond first relapse (HR 0.95; 95% CI 0.42-2.12; P=0.89); 7.1 months in pts <65 yrs and 7.6 months in those ≥65 yrs of age (HR 0.84; 95% CI 0.37-1.92; P=0.68). Median OS was NR. No new safety concerns were observed. TP53 mutational analysis is underway. Conclusion: In this difficult-to-treat population, DPd is a therapeutic option for pts of all ages and can be considered as a bridge to other immunotherapies, such as T-cell engagers and CAR-T cells.